DOCSLIB.ORG

Cytochrome P450 2C19 (CYP2C19) Pharmacogenetic Competency

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cytochrome P450 2C19 (CYP2C19) Pharmacogenetic Competency Cytochrome P450 2C19 (CYP2C19) Pharmacogenetic Competency Updated on 6/2015 Pre-test Question # 1 A patient has a reported pharmacogenetic test result of CYP2C19 *1/*12. What is the assigned phenotype? a) Ultra-rapid metabolizer (UM) b) Intermediate metabolizer (IM) c) Poor metabolizer (PM) d) Indeterminate Pre-test Question # 2 A patient with a reported pharmacogenetic test result of CYP2C19 *2A/*2A who is receiving clopidogrel is at risk of suffering from an adverse cardiovascular event (e.g. thrombosis) due to treatment failure. a) Increased b) Moderate c) Decreased Pre-test Question # 3 JH has an indication to start clopidogrel therapy. He has a reported pharmacogenetic test result of CYP2C19 *2A/*3. What is your recommendation to the physician regarding the use of clopidogrel? a) Use clopidogrel at an increased dose b) Use clopidogrel at a reduced dose c) Use clopidogrel at a standard dose d) Use an alternative antiplatelet agent Pre-test Question # 4 Which of the following statements is most correct about a CYP2C19 *17/*17 genotype? a) Patients convert clopidogrel to an inactive metabolite to a greater extent than *1/*1 and therefore a decrease in clopidogrel dose is recommended b) Patients convert clopidogrel to an active metabolite to a greater extent than *1/*1 but no change in clopidogrel dose is recommended c) Patients convert clopidogrel to an active metabolite to a lesser extent than *1/*1 and therefore a decrease in clopidogrel dose is recommended d) Patients convert clopidogrel to an active metabolite to a lesser extent than *1/*1 and therefore a change in therapy is recommended Objectives • Upon completion of this competency, participants will be able to: – Recognize the different CYP2C19 allele variants – Describe the different CYP2C19 phenotypes – Assign the correct phenotype based upon the allele variants – Make therapeutic recommendations for clopidogrel dosing based on a patient's predicted CYP2C19 phenotype Patient Case • A 74-year-old patient with severe coronary artery disease started on clopidogrel following a percutaneous coronary intervention (PCI). • After multiple episodes of restenosis, clopidogrel resistance was suspected. • Platelet reactivity testing measured while on clopidogrel returned was high (suggestive of resistance). • CYP2C19 genotyping revealed that the patient was homozygous for two non-functional alleles (*2/*2 genotype). The patient was classified as having a CYP2C19 poor metabolizer phenotype. • Switched to prasugrel, reduction in platelet reactivity by 86% and no cardiovascular events since switching agents. Rai M, et al. Conn Med. 2012;76(5):267-72. CYP2C19 Pharmacogenetics CYP2C19 • CYP2C19 is an enzyme that metabolizes some commonly prescribed drugs • Metabolism by CYP2C19 can either activate or inactivate a drug – Clopidogrel is a prodrug that is metabolized to an active form by CYP2C19 – Amitriptyline is metabolized by CYP2C19 to a less active form CYP2C19 • Genetic variations in the CYP2C19 gene may lead to changes in metabolic activity of the CYP2C19 enzyme (increased or reduced function) CYP2C19 Allele Variants • CYP2C19 alleles are characterized into different groups: – Wild-type (normal function) alleles – Reduced function alleles – Increased function alleles – Uncharacterized alleles CYP2C19 Allele Variants • CYP2C19 wild-type (normal function) allele: – This allele encodes for CYP2C19 enzymes with normal metabolic function – *1 Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants • Certain CYP2C19 alleles are characterized as reduced function alleles – These alleles will encode for a CYP2C19 enzyme that has little or no metabolic function • Reduced function CYP2C19 alleles include: – *2,*2A, *2B, *3, *4, *5, *6, *7, *8 Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants • CYP2C19 has an allele characterized by a increased expression of the enzyme – This results in increased CYP2C19 metabolic activity compared to the wild-type (normal function) allele • The CYP2C19 gain-of-function allele that is test for the most in clinical practice is the *17 allele Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Allele Variants • For certain CYP2C19 alleles, the function of the enzyme is unknown and considered uncharacterized • CYP2C19 uncharacterized alleles include: – *9, *10, *12, *13, *14,*15 Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. www.pharmgkb.org Assigning a CYP2C19 Phenotype CYP2C19 Phenotypes • The assignment of CYP2C19 phenotype is based on the two alleles that the patient carries (also called genotype or diplotype) • There are four CYP2C19 phenotypes — Ultra-rapid metabolizer (UM) — Extensive metabolizer (EM) — Intermediate metabolizer (IM) — Poor metabolizer (PM) Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. CYP2C19 Phenotypes Phenotype Definition • Two copies of an increased function allele. Ultra-rapid • One copy of a normal function allele and one copy of an increased function Metabolizer (UM) allele. Extensive Metabolizer • Two copies of a normal function allele. (EM) • One copy of a reduced function allele and one copy of a normal function Intermediate allele. Metabolizer (IM) • One copy of an increased function allele (*17) with one copy of a reduced function allele (either *2, *2A and *2B).1 Poor Metabolizer • Two copies of a reduced function allele. (PM) • Two copies of an indeterminate function allele. • One copy of an indeterminate function allele with one copy of a known Indeterminate function allele. • One copy of an increased function allele with one copy of a reduced function allele (other than *2, *2A and *2B). 1. As per the CYP2C19/Clopidogrel CPIC guideline update (2013): The currently available evidence indicates that the *17 gain-of-function allele is unable to completely compensate for the *2 loss-of-function allele; however, these data have not been consistently replicated and is therefore a provisional classification. CYP2C19 Phenotypes • Ultra-rapid Metabolizers (UM) — Have CYP2C19 enzyme function higher than normal — Approximately 17% of the population — Diplotype examples: • *17/*17 • *1/*17 CYP2C19 Phenotypes • Extensive (normal) metabolizers (EM) — Have normal CYP2C19 enzyme function — Homozygous wild-type/normal — Approximately 43% of the population — Patient carrying two functional alleles — Diplotype examples: • *1/*1 CYP2C19 Phenotypes • Intermediate metabolizers (IM) — Have decreased CYP2C19 enzyme function. The activity is in between extensive and poor metabolizer patients — Approximately 30% of the population — Diplotype examples: • *1/*2A • *2A/*17 CYP2C19 Phenotypes • Poor metabolizers (PM) — Have little or no CYP2C19 enzyme function — Approximately 10% of the population — Patient carrying two reduced-function alleles — Diplotype examples: • *2A/*2A • *2A/*2B CYP2C19 Phenotypes • Indeterminate • The expected phenotype cannot be determined based upon the CYP2C19 genotype result • For example, a patient may have two copies of an indeterminate function allele or one copy of an indeterminate function allele and one copy of a known function allele • *1/*12 • *12/*14 CYP2C19 Phenotypes • Phenotypes associated with *17 allele – Only a few diplotypes which include the *17 allele have known functional activity: • *1/*17 is assigned an ultra-rapid metabolizer phenotype • *2/*17,*2A/*17 and *2B/*17 are assigned an intermediate function phenotype – *17 plus any other allele is assigned an indeterminate phenotype CYP2C19 Phenotypes Ultrarapid Metabolizer- very high activity 10% 17% Extensive Metabolizer-normal activity 30% Intermediate Metabolizer- lower activity 43% Poor Metabolizer- low or no activity * The exact percent of each phenotype group varies by ethnicity CYP2C19 Phenotypes • CYP2C19 allele frequencies are dependent on ethnicity • *2 and *3 alleles are the most common variations – *2 allele: • ~30% of Asians • ~15% of Caucasians and African-Americans – *3 allele: • ~8% of Asians • Less than 1% in Caucasians and African-Americans • Prevalence of poor metabolizer phenotype: – Up to 25% of Asians – ~5% of Caucasians and African-Americans Gene-Based Dosing Recommendations Clopidogrel Clopidogrel • Clopidogrel is an antiplatelet drug which inhibits ADP-induced platelet aggregation • Clopidogrel is commonly used in patients undergoing percutaneous coronary intervention (PCI) with stent placement • Other indications: – Acute coronary syndrome (ACS) – Stroke – Peripheral artery disease • The 2013 CPIC guideline on clopidogrel and CYP2C19 mainly focuses on ACS/PCI patients Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. Clopidogrel • Clopidogrel is a pro-drug that requires hepatic bioactivation – 85% of the drug is hydrolyzed by carboxylesterase 1, leaving only 15% to be converted to the active form • The activation of clopidogrel is a two step process – Clopidogrel is converted to 2-oxoclopidogrel via CYP2C19 (45%), CYP1A2 (36%), and CYP2B6 (19%) – 2-oxoclopidogrel is converted to the active thiol metabolite via CYP3A4/5 (40%), CYP2B6 (33%), CYP2C19 (21%), and CYP2C9 (7%) Scott SA, et al. Clin Pharmacol Ther. 2013;94(3):317-23. Kazui M, et al. Drug Metab Dispos. 2010;38:92-99. Clopidogrel 45% 21% Sangkuhl K, et al. Pharmacogenet Genomics 2010;20:463-465. Clopidogrel • Clopidogrel’s anti-platelet effect is closely related to CYP2C19 metabolism – Ultra-rapid metabolizers • Convert clopidogrel to the active metabolite at a greater extent than normal • Possible increase in antiplatelet activity • No recommended dosage change – Extensive
Load more

Recommended publications
  • SINGLE CATEGORY MEDICATION REPORTS Quick Reference List
    SINGLE CATEGORY MEDICATION REPORTS Quick Reference List PAIN MEDICATION CARDIOVASCULAR REPORT MEDICATION REPORT Opioid Beta NSAIDs Other Statins Other Analgesics Blockers Celecoxib Codeine Amitriptyline Atorvastatin Metoprolol Acenocoumarol Flurbiprofen Hydrocodone Duloxetine Fluvastatin Clopidogrel Ibuprofen Morphine Nortriptyline Simvastatin Flecainide Meloxicam Oxycodone Irbesartan Piroxicam Tramadol Losartan Propafenone Warfarin GASTROINTESTINAL MENTAL HEALTH MEDICATION REPORT MEDICATION REPORT Proton Pump Anti-Emetics Antidepressants Antipsychotics Other Inhibitors Amitriptyline Fluoxetine Paroxetine Aripiprazole Atomoxetine Dexlansoprazole Metoclopramide Citalopram Fluvoxamine Sertraline Brexpiprazole Clobazam Esomeprazole Ondansetron Clomipramine Imipramine Venlafaxine Chlorpromazine Diazepam Lansoprazole Desipramine Mirtazapine Vortioxetine Clozapine Melatonin Omeprazole Doxepin Moclobemide Haloperidol Pantoprazole Duloxetine Nortriptyline Olanzapine Rabeprazole Escitalopram Pimozide Quetiapine Risperidone Zuclopenthixol For all enquiries contact myDNA clinical support on 1844 472 7896 or email [email protected] HEALTH CARE PROFESSIONAL REPORTS Medication List Below is a list of the main medications covered by the myDNA Medication Test (grouped by the gene which primarily impacts the medication response). Note: CYP450 enzymes generally metabolise pharmacologically active drugs into less active metabolite(s). Conversely, prodrugs are pharmacologically inactive, and are converted into active metabolite(s). CYP2D6 SLCO1B1 Beta Opioid
    [Show full text]
  • Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 231 _____________________________ _____________________________ Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21 BY JOHAN BYLUND ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2000 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Pharmaceutical Pharmacology presented at Uppsala University in 2000 ABSTRACT Bylund, J. 2000. Cytochrome P450 Enzymes in Oxygenation of Prostaglandin Endoperoxides and Arachidonic Acid: Cloning, Expression and Catalytic Properties of CYP4F8 and CYP4F21. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from Faculty of Pharmacy 231 50 pp. Uppsala. ISBN 91-554-4784-8. Cytochrome P450 (P450 or CYP) is an enzyme system involved in the oxygenation of a wide range of endogenous compounds as well as foreign chemicals and drugs. This thesis describes investigations of P450-catalyzed oxygenation of prostaglandins, linoleic and arachidonic acids. The formation of bisallylic hydroxy metabolites of linoleic and arachidonic acids was studied with human recombinant P450s and with human liver microsomes. Several P450 enzymes catalyzed the formation of bisallylic hydroxy metabolites. Inhibition studies and stereochemical analysis of metabolites suggest that the enzyme CYP1A2 may contribute to the biosynthesis of bisallylic hydroxy fatty acid metabolites in adult human liver microsomes. 19R-Hydroxy-PGE and 20-hydroxy-PGE are major components of human and ovine semen, respectively. They are formed in the seminal vesicles, but the mechanism of their biosynthesis is unknown. Reverse transcription-polymerase chain reaction using degenerate primers for mammalian CYP4 family genes, revealed expression of two novel P450 genes in human and ovine seminal vesicles.
    [Show full text]
  • Pgx - Cytochrome P450 2C19 (CYP2C19)
    PGx - Cytochrome P450 2C19 (CYP2C19) This assay is used to identify patients who may be at risk for altered metabolism of drugs that are modified by CYP2C19. Cytochrome P450 (CYP) isozyme 2C19 is responsible for phase I metabloism of about 40% of drugs including: clopidogrel, phenytoin, diazepam, R-warfarin, tamoxifen, some antidepressants, proton pump inhibitors, and antimalarials. Testing Method and Background This test utilizes the eSensor® 2C19 Genotyping Test is an in vitro diagnostic for the detection and genotyping a panel of variants involved with enzyme metabolism using isolated genomic DNA. The eSensor® technology uses a solid-phase electrochemical method for determining the genotyping status. The eSensor® 2C19 Genotyping Test is for research use only (RUO). CYP2C19 drug metabolism varies among individuals depending on specific genotype. The CYP2 family has many single- nucleotide polymorphisms (SNPs). CYP2C19 gene is located on chromosome 10q23.33 and is highly polymorphic, which can lead to large individual variation in CYP2C19 enzyme activity and related drug response phenotypes and/or undesired adverse drug events. Specifically, the CYP2C19 gene has more than 34 variant alleles identified, which in turn affects the pharmacokinetics of many drugs. Highlights of PGx - Cytochrome P450 2C19 (CYP2C19) Targeted Region CYP2C19: Detects 11 variants/polymorphisms 681G>A (*2) 636G>A (*3) 1A>G (*4) 1297C>T (*5) 395G>A (*6) 19294T>A (*7) 358T>C (*8) 431G>A (*9) 680C>T (*10) 1228C>T (*13) -806C>T (*17) Ordering Information Get started
    [Show full text]
  • Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin
    Supplemental material to this article can be found at: http://dmd.aspetjournals.org/content/suppl/2018/01/17/dmd.117.078428.DC1 1521-009X/46/4/367–379$35.00 https://doi.org/10.1124/dmd.117.078428 DRUG METABOLISM AND DISPOSITION Drug Metab Dispos 46:367–379, April 2018 Copyright ª 2018 by The American Society for Pharmacology and Experimental Therapeutics Polymorphic Human Sulfotransferase 2A1 Mediates the Formation of 25-Hydroxyvitamin D3-3-O-Sulfate, a Major Circulating Vitamin D Metabolite in Humans s Timothy Wong, Zhican Wang, Brian D. Chapron, Mizuki Suzuki, Katrina G. Claw, Chunying Gao, Robert S. Foti, Bhagwat Prasad, Alenka Chapron, Justina Calamia, Amarjit Chaudhry, Erin G. Schuetz, Ronald L. Horst, Qingcheng Mao, Ian H. de Boer, Timothy A. Thornton, and Kenneth E. Thummel Departments of Pharmaceutics (T.W., Z.W., B.D.C., M.S., K.G.C., C.G., B.P., Al.C., J.C., Q.M., K.E.T.), Medicine and Kidney Research Institute (I.H.d.B.), and Biostatistics (T.A.T.), University of Washington, Seattle, Washington; Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., South San Francisco, California (Z.W.); Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., Cambridge, Massachusetts (R.S.F.); St. Jude Children’s Research Hospital, Memphis, Tennessee Downloaded from (Am.C., E.G.S.); and Heartland Assays LLC, Ames, Iowa (R.L.H.) Received September 1, 2017; accepted January 10, 2018 ABSTRACT dmd.aspetjournals.org Metabolism of 25-hydroxyvitamin D3 (25OHD3) plays a central role in with the rates of dehydroepiandrosterone sulfonation. Further analysis regulating the biologic effects of vitamin D in the body.
    [Show full text]
  • Frequencies of Clinically Important CYP2C19 and CYP2D6 Alleles Are Graded Across Europe
    European Journal of Human Genetics (2020) 28:88–94 https://doi.org/10.1038/s41431-019-0480-8 ARTICLE Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe 1,2 2 1 Jelena Petrović ● Vesna Pešić ● Volker M. Lauschke Received: 15 March 2019 / Revised: 3 July 2019 / Accepted: 17 July 2019 / Published online: 29 July 2019 © The Author(s) 2019. This article is published with open access Abstract CYP2C19 and CYP2D6 are important drug-metabolizing enzymes that are involved in the metabolism of around 30% of all medications. Importantly, the corresponding genes are highly polymorphic and these genetic differences contribute to interindividual and interethnic differences in drug pharmacokinetics, response, and toxicity. In this study we systematically analyzed the frequency distribution of clinically relevant CYP2C19 and CYP2D6 alleles across Europe based on data from 82,791 healthy individuals extracted from 79 original publications and, for the first time, provide allele confidence intervals for the general population. We found that frequencies of CYP2D6 gene duplications showed a clear South-East to North- West gradient ranging from <1% in Sweden and Denmark to 6% in Greece and Turkey. In contrast, an inverse distribution was observed for the loss-of-function alleles CYP2D6*4 and CYP2D6*5. Similarly, frequencies of the inactive CYP2C19*2 allele were graded from North-West to South-East Europe. In important contrast to previous work we found that the increased activity allele CYP2C19*17 was most prevalent in Central Europe (25–33%) with lower prevalence in Mediterranean-South Europeans (11–24%). In summary, we provide a detailed European map of common CYP2C19 and CYP2D6 variants and find that frequencies of the most clinically relevant alleles are geographically graded reflective of Europe’s migratory history.
    [Show full text]
  • ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential
    pharmaceuticals Review ADME and Pharmacokinetic Properties of Remdesivir: Its Drug Interaction Potential Subrata Deb * , Anthony Allen Reeves, Robert Hopefl and Rebecca Bejusca Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (R.H.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +224-310-7870 Abstract: On 11 March 2020, the World Health Organization (WHO) classified the Coronavirus Disease 2019 (COVID-19) as a global pandemic, which tested healthcare systems, administrations, and treatment ingenuity across the world. COVID-19 is caused by the novel beta coronavirus Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Since the inception of the pandemic, treatment options have been either limited or ineffective. Remdesivir, a drug originally designed to be used for Ebola virus, has antiviral activity against SARS-CoV-2 and has been included in the COVID-19 treatment regimens. Remdesivir is an adenosine nucleotide analog prodrug that is metabolically activated to a nucleoside triphosphate metabolite (GS-443902). The active nucleoside triphosphate metabolite is incorporated into the SARS-CoV-2 RNA viral chains, preventing its replication. The lack of reported drug development and characterization studies with remdesivir in public domain has created a void where information on the absorption, distribution, metabolism, elimination (ADME) properties, pharmacokinetics (PK), or drug-drug interaction (DDI) is limited. By Citation: Deb, S.; Reeves, A.A.; understanding these properties, clinicians can prevent subtherapeutic and supratherapeutic levels of Hopefl, R.; Bejusca, R. ADME and remdesivir and thus avoid further complications in COVID-19 patients. Remdesivir is metabolized Pharmacokinetic Properties of by both cytochrome P450 (CYP) and non-CYP enzymes such as carboxylesterases.
    [Show full text]
  • Cytochrome P450 2C19 Loss-Of-Function Polymorphism Is Associated with an Increased Treatment-Related Mortality in Patients Undergoing Allogeneic Transplantation
    Bone Marrow Transplantation (2007) 40, 659–664 & 2007 Nature Publishing Group All rights reserved 0268-3369/07 $30.00 www.nature.com/bmt ORIGINAL ARTICLE Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation AH Elmaagacli, M Koldehoff, NK Steckel, R Trenschel, H Ottinger and DW Beelen Department of Bone Marrow Transplantation, University Hospital of Essen, Essen, Germany The polymorphic gene expression of CYP2C19 causes characterized enzymes with a large number of genetic individual variability in drug metabolism and thereby in polymorphisms is cytochrome P450 (CYP) 2C19.1 Pre- pharmacologic and toxicologic responses. We genotyped vious studies on CYP2C19 using probe drugs such as 286 patients and their donors for the CYP2C19 gene who S-mephenytoin showed that individuals could be classified underwent allogeneic transplantation for various diseases into three different groups: poor metabolizers (PMs), and analyzed their outcome. Patients were classified as: intermediate metabolizers (IMs) and extensive metabolizers poor metabolizers (PMs; 3.1%), intermediate metaboli- (EMs). PMs have a genetically determined absence of active zers (IMs; 24.5%) and extensive metabolizers (EMs; enzymes, which is the cause for a slower metabolism of 72.5%). Patients genotyped as PMs had significant higher active drugs and is associated with prolonged side effects.1 hepato- and nephrotoxicities compared to IMs or EMs. If prodrugs are applied, the metabolism in their active form Maximum bilirubin and serum creatinine levels measured is delayed and reduced effectiveness may occur. Among the after transplant were approximately twofold higher than drugs which are metabolized by CYP2C19 enzymes are those of EMs or IMs.
    [Show full text]
  • The Effect of CYP2B6, CYP2D6, and CYP3A4 Alleles on Methadone Binding: a Molecular Docking Study
    Hindawi Publishing Corporation Journal of Chemistry Volume 2013, Article ID 249642, 7 pages http://dx.doi.org/10.1155/2013/249642 Research Article The Effect of CYP2B6, CYP2D6, and CYP3A4 Alleles on Methadone Binding: A Molecular Docking Study Nik Nur Syazana Bt Nik Mohamed Kamal,1 Theam Soon Lim,1 Gee Jun Tye,1 Rusli Ismail,2 and Yee Siew Choong1 1 Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, 11800 Minden, Penang, Malaysia 2 Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia Correspondence should be addressed to Yee Siew Choong; [email protected] Received 7 May 2013; Revised 23 July 2013; Accepted 5 August 2013 Academic Editor: Hugo Verli Copyright © 2013 Nik Nur Syazana Bt Nik Mohamed Kamal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Current methadone maintenance therapy (MMT) is yet to ensure 100% successful treatment as the optimum dosage has yet to be determined. Overdose leads to death while lower dose causes the opioid withdrawal effect. Single-nucleotide polymorphisms (SNP) in cytochrome P450s (CYPs), the methadone metabolizers, have been showen to be the main factor for the interindividual variability of methadone clinical effects. In this study, we investigated the effect of SNPs in three major methadone metabolizers ∗ ∗ ∗ (CYP2B6, CYP2D6, and CYP3A4) on methadone binding affinity. Results showed that CYP2B6 11, CYP2B6 12, CYP2B6 18,and ∗ CYP3A4 12 have significantly higher binding affinity to R-methadone compared to wild type.
    [Show full text]
  • The Clinical Toxicology of Gamma-Hydroxybutyrate, Gamma-Butyrolactone and 1,4-Butanediol
    Clinical Toxicology (2012), 50: 458–470 Copyright © 2012 Informa Healthcare USA, Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10.3109/15563650.2012.702218 REVIEW ARTICLE The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol LEO J SCHEP 1 , KAI KNUDSEN 2 , ROBIN J SLAUGHTER 1 , J ALLISTER VALE 3 , and BRUNO MÉGARBANE 4 1 National Poisons Centre, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand 2 Department of Anesthesia and Intensive Care Medicine, Surgical Sciences, Blå Stråket 5, Sahlgrenska University Hospital, Gothenburg, Sweden 3 National Poisons Information Service (Birmingham Unit) and West Midlands Poisons Unit, City Hospital, Birmingham, UK; School of Biosciences and College of Medical and Dental Sciences, University of Birmingham, Birmingham,UK 4 Hôpital Lariboisière, Réanimation Médicale et Toxicologique, INSERM U705, Université Paris-Diderot, Paris, France Introduction. Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. Methods. OVID MEDLINE and ISI Web of Science databases were searched using the terms “ GHB, ” “ gamma-hydroxybutyrate, ” “ gamma-hydroxybutyric acid, ” “ 4-hydroxybutanoic acid, ” “ sodium oxybate, ” “ gamma-butyrolactone, ” “ GBL, ” “ 1,4-butanediol, ” and “ 1,4-BD ” alone and in combination with the keywords “ pharmacokinetics, ” “ kinetics, ” “ poisoning, ” “ poison, ” “ toxicity, ” “ ingestion, ” “ adverse effects, ” “ overdose, ” and “ intoxication.
    [Show full text]
  • Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives
    pharmaceuticals Article Simulation of Physicochemical and Pharmacokinetic Properties of Vitamin D3 and Its Natural Derivatives Subrata Deb * , Anthony Allen Reeves and Suki Lafortune Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL 33169, USA; [email protected] (A.A.R.); [email protected] (S.L.) * Correspondence: [email protected] or [email protected]; Tel.: +1-224-310-7870 or +1-305-760-7479 Received: 9 June 2020; Accepted: 20 July 2020; Published: 23 July 2020 Abstract: Vitamin D3 is an endogenous fat-soluble secosteroid, either biosynthesized in human skin or absorbed from diet and health supplements. Multiple hydroxylation reactions in several tissues including liver and small intestine produce different forms of vitamin D3. Low serum vitamin D levels is a global problem which may origin from differential absorption following supplementation. The objective of the present study was to estimate the physicochemical properties, metabolism, transport and pharmacokinetic behavior of vitamin D3 derivatives following oral ingestion. GastroPlus software, which is an in silico mechanistically-constructed simulation tool, was used to simulate the physicochemical and pharmacokinetic behavior for twelve vitamin D3 derivatives. The Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) Predictor and PKPlus modules were employed to derive the relevant parameters from the structural features of the compounds. The majority of the vitamin D3 derivatives are lipophilic (log P values > 5) with poor water solubility which are reflected in the poor predicted bioavailability. The fraction absorbed values for the vitamin D3 derivatives were low except for calcitroic acid, 1,23S,25-trihydroxy-24-oxo-vitamin D3, and (23S,25R)-1,25-dihydroxyvitamin D3-26,23-lactone each being greater than 90% fraction absorbed.
    [Show full text]
  • Clinical Pharmacology and Biopharmaceutics Review(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 200327 CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW(S) CLINICAL PHARMACOLOGY REVIEW NDA: 200-327 Submission Date(s): • 30 Dec 2009 (SDN 1) • 30 Apr 2010 (SDN 14) • 04 Feb 2010 (SDN 7) • 18 Jun 2010 (SDN 19) • 23 Apr 2010 (SDN 10) • 06 Aug 2010 (SDN 31) • 29 Apr 2010 (SDN 13) • 18 Aug 2010 (SDN 34) Drug Ceftaroline Fosamil for Injection Trade Name TEFLARO™ (proposed) OCP Reviewer Aryun Kim, Pharm.D. OCP Team Leader Charles Bonapace, Pharm.D. PM Reviewer Yongheng Zhang, Ph.D. PM Team Leader Pravin Jadhav, Ph.D. OCP Division DCP4 OND division DAIOP (520) Sponsor Cerexa, Inc., Oakland, CA Relevant IND(s) IND 71,371 Submission Type; Code Original New Drug Application (New Molecular Entity), 1S Formulation; Strength(s) Sterile (b) (4) of ceftaroline fosamil and L-arginine supplied as powder in single-use, 20-cc, clear, Type I glass vials containing 600 mg or 400 mg of ceftaroline fosamil Indication For the treatment of complicated skin and skin structure infections (cSSSI) and community-acquired bacterial pneumonia (CABP) caused by designated susceptible isolates of Gram-positive and Gram-negative microorganisms Dosage and 600 mg administered every 12 hours by intravenous infusion over 1 hour Administration in patients ≥18 years of age • for 5-14 days for treatment of cSSSI • for 5-7 days for treatment of CABP 1. EXECUTIVE SUMMARY 5 1.1 Recommendations 5 1.2 Phase 4 Commitments 6 1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics Findings 6 2. QUESTION-BASED REVIEW 11 2.1 General Attributes of the Drug 11 2.2 General Clinical Pharmacology 13 2.3 Intrinsic Factors 37 2.4 Extrinsic Factors 56 2.5 General Biopharmaceutics 58 2.6 Analytical Section 58 3.
    [Show full text]
  • Variation in CYP2A6 Activity and Personalized Medicine
    Journal of Personalized Medicine Review Variation in CYP2A6 Activity and Personalized Medicine Julie-Anne Tanner 1,2 and Rachel F. Tyndale 1,2,3,* 1 Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada; [email protected] 2 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada 3 Department of Psychiatry, University of Toronto, Toronto, ON M5T 1R8, Canada * Correspondence: [email protected]; Tel.: +1-416-978-6374; Fax: +1-416-978-6395 Academic Editor: Stephen B. Liggett Received: 7 October 2017; Accepted: 27 November 2017; Published: 1 December 2017 Abstract: The cytochrome P450 2A6 (CYP2A6) enzyme metabolizes several clinically relevant substrates, including nicotine—the primary psychoactive component in cigarette smoke. The gene that encodes the CYP2A6 enzyme is highly polymorphic, resulting in extensive interindividual variation in CYP2A6 enzyme activity and the rate of metabolism of nicotine and other CYP2A6 substrates including cotinine, tegafur, letrozole, efavirenz, valproic acid, pilocarpine, artemisinin, artesunate, SM-12502, caffeine, and tyrosol. CYP2A6 expression and activity are also impacted by non-genetic factors, including induction or inhibition by pharmacological, endogenous, and dietary substances, as well as age-related changes, or interactions with other hepatic enzymes, co-enzymes, and co-factors. As variation in CYP2A6 activity is associated with smoking behavior, smoking cessation, tobacco-related lung cancer risk, and with altered metabolism and resulting clinical responses for several therapeutics, CYP2A6 expression and enzyme activity is an important clinical consideration. This review will discuss sources of variation in CYP2A6 enzyme activity, with a focus on the impact of CYP2A6 genetic variation on metabolism of the CYP2A6 substrates.
    [Show full text]